IMPACT OF REAL-LIFE ENVIRONMENTAL EXPOSURES ON REPRODUCTION: Rodent reproductive behavior among males and females after exposure to endocrine-disrupting chemicals

Abstract

In brief: The rodent reproductive behavioral control column of the hypothalamus and the hypothalamic-pituitary-gonadal (HPG) axis are critical systems that regulate copulatory behaviors in both males and females. We review how endocrine-disrupting chemicals (EDCs), specifically phthalates, bisphenol A, and chemical mixtures, dysregulate appetitive and consummatory copulatory behaviors and their neuroendocrine substrates, using mouse and rodent models.

Abstract: Sexual reproduction - from both physiological and behavioral perspectives - is dependent upon appropriate connections between a diverse, hormone-modulated network of neural regions. Importantly, these substrates are regulated by hormones across the lifespan from early development to adulthood, making them targets of EDCs. Rodents, such as mice and rats, are invaluable to the characterization of EDCs because of their sex-specific, stereotyped appetitive and consummatory reproductive behaviors. Phthalates, bisphenol A (BPA), and EDC mixtures pose a salient risk to the health of humans, wildlife, and livestock because these synthetic compounds are ubiquitous due to their widespread use in the mass production of consumer and industrial goods. This review outlines how the HPG axis regulates male and female sexual behaviors, and how phthalates and BPA can perturb appetitive and consummatory behaviors and impact neural substrates that modulate reproductive behavior. We will then discuss how to progress toward a clearer understanding of the reproductive and neurobiological changes that occur due to EDC exposure.

Figure 1.

The female hypothalamic-pituitary-gonadal (HPG) axis is a major pathway modulating copulatory receptivity in female rodents. Thus, each HPG component is susceptible to harm from endocrine disrupting chemicals (EDCs). Cyclic feedback across this system establishes the appropriate hormonal context which enables rodent expression of consummatory lordosis. The symbols + and – represent positive and negative feedback actions, respectively. Kisspeptin (kiss) neurons in the anteroventral periventricular nucleus (AVPV) and arcuate (ARC) integrate sex-hormone signals originating from the ovary. The AVPV and ARC transduce these integrated ovarian signals and stimulate neurons which release gonadotropin releasing hormone (GnRH). This release of GnRH can occur in a pulsatile or surge manner. The GnRH signal then stimulates the anterior pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These releasing hormones act on receptors on the ovary which maintains the continuing reproductive cycle.

Figure 2.

The male hypothalamic pituitary gonadal axis (HPG) is a connected system of reproductive structures which regulate reproductive behavior. Each aspect of the HPG axis is a potential target of endocrine disrupting chemical (EDC) action, requiring further study. The – symbols represent negative feedback functions. Functions of the male HPG axis, similar to the female counterpart, are reliant upon hypothalamic GnRH neurons. However, a major dimorphism in the HPG axis is the hypothalamic regulation of GnRH and LH release. Specifically, in rodents, only females demonstrate LH surge signaling and strong positive feedback of gonadal hormones on the hypothalamus. Abbreviations: ARC; Arcuate, AVPV; anteroventral periventricular nucleus, FSH; Follicle-stimulating hormone, GnRH; gonadotropin releasing hormone, LH, Luteinizing hormone.

Figure 3.

Male reproductive consummation occurs when the male (brown mouse) grasps the flanks of the female (grey mouse), thrusts his pelvis, and intromits his penis into her vagina. Male copulation depends on the MPOA and VMHvl of the RBCC. In contrast to females the PMv does not regulate reproductive behavior (Mei et al., 2023; Wei et al., 2021). The excitatory (glutamatergic) and inhibitory (GABAergic) connections in this circuit connect hormone-sensitive nuclei and require further investigation with respect to EDCs. Most interesting, Bayless et al., 2023 report that GABAergic projections from the BNST to the MPOA are initially inhibitory but become excitatory. Abbreviations: BNSTp; Bed nucleus of the stria terminalis, posterior part; GABA; Gamma-aminobutyric acid; MeA; Medial amygdala; MPOA; Medial preoptic area; RBCC; Reproductive behavioral control column; VMHvl; Ventromedial hypothalamus, ventrolateral part.

Figure 4.

The female rodent (grey) expresses lordosis, i.e., sexual receptivity, characterized by a back in dorsiflexion that facilitates intromission from the male (brown). Lordosis is regulated via glutamatergic (excitatory) and GABAergic (inhibitory) connections across the MPOA, VHMvll, and PMv of the reproductive behavioral control column (Yin & Lin, 2023). Chemosensory social cues, such as male pheromones and volatile odors, transduced via the BNSTpr and MeA, are upstream regulators of the RBCC. The MPOA suppresses lordosis, while the VMHvll promotes lordosis (Mei et al., 2023). The PMv also promotes lordosis, though less so than the VMHvll (Mei et al., 2023). Changes in the balance of activation of these nuclei modulates female sexual receptivity. Each of these nuclei and their connections is an area requiring further exploration, regarding EDCs. Abbreviations: BNSTpr; Bed nucleus of the stria terminalis, principal nucleus, GABA; Gamma-aminobutyric acid, MeA; Medial amygdala, MPOA; Medial preoptic area, PAG; Periaqueductal gray, PMv; Ventral premammillary nucleus, VMHvll; Ventromedial hypothalamus, ventrolateral part, lateral subdivision.